JWA loss promotes cell migration and cytoskeletal rearrangement by affecting HER2 expression and identifies a high-risk subgroup of HER2-positive gastric carcinoma patients
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Jing Qian1, Weiyou Zhu1, Keming Wang2, Lin Ma1, Jin Xu3, Tongpeng Xu1, Oluf Dimitri Røe4,5, Aiping Li3, Jianwei Zhou3, Yongqian Shu1
1Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Department of Oncology, The Secondary Affiliated Hospital of Nanjing Medical University, Nanjing, China
3Department of Molecular Cell Biology and Toxicology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
4Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
5Department of Clinical Medicine, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
Yongqian Shu, email: firstname.lastname@example.org
Keywords: gastric cancer, HER2, cell migration, JWA, PEA3
Received: May 19, 2015 Accepted: April 23, 2016 Published: May 6, 2016
Background and Aims: JWA, a microtubule-associated protein (MAP) involved in apoptosis, has been identified as a suppressor of metastasis, and it affects cell migration in melanoma and its downregulation in tumor is an idependent negative prognostic factor in resectable gastric cancer. HER2 overexpression has been observed in gastric cancer (GC) cells and implicated in the metastatic phenotype. However, the biological role of JWA in migration and its clinical value in HER2-positive GC remain elusive.
Results: JWA suppresses EGF-induced cell migration and actin cytoskeletal rearrangement by abrogating HER2 expression and downstream PI3K/AKT signaling in HER2-overexpressing GC cell lines. The modulation of HER2 by JWA is dependent on ERK activation and consequent PEA3 upregulation and activation. Reduced JWA expression is associated with high HER2 expression and with poor survival in patients with AGC, whereas HER2 expression alone is not associated with survival. However, concomitant low JWA and high HER2 expression is associated with unfavorable outcomes. Additionally, when patients were stratified by JWA expression, those with higher HER2 expression in the low JWA expression subgroup exhibited worse survival.
Methods: The impact of JWA on the EGF-induced migration of HER2-positive GC cells was studied using transwell assays and G-LISA assays. Western blotting, real-time PCR, electrophoretic mobility shift assays and luciferase assays were utilized to investigate the mechanisms by which JWA affects HER2. The association of JWA with HER2 and its clinical value were further analyzed by IHC in 128 pairs of advanced gastric cancer (AGC) and adjacent normal tissue samples.
Conclusions: This study characterizes a novel mechanism for regulating cell motility in HER2-overexpressing GC cells involving JWA-mediated MEK/ERK/PEA3 signaling activation and HER2 downregulation. Furthermore, JWA may be a useful prognostic indicator for advanced GC and may help stratify HER2-positive patient subgroups to better identify unfavorable outcomes.
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